期刊
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
卷 25, 期 22, 页码 5115-5120出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2015.10.009
关键词
Metabotropic glutamate receptor 5 (mGlu(5)); Positive allosteric modulator (PAM)
资金
- NIH [NS031373, MH062646]
- Janssen, The Pharmaceutical Companies of Johnson Johnson
We report the optimization of a series of metabotropic glutamate receptor 5 (mGlu(5)) positive allosteric modulators (PAMs) from an acyl dihydropyrazolo[1,5-a]pyrimidinone class. Investigation of exocyclic amide transpositions with this unique 5,6-bicyclic core were conducted in attempt to modulate physicochemical properties and identify a suitable backup candidate with a reduced half-life. A potent and selective PAM, 1-(2-(phenoxymethyl)-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl) ethanone (9a, VU0462807), was identified with superior solubility and efficacy in the acute amphetamine-induced hyperlocomotion (AHL) rat model with a minimum effective dose of 3 mg/kg. Attempts to mitigate oxidative metabolism of the western phenoxy of 9a through extensive modification and profiling are described. (C) 2015 Elsevier Ltd. All rights reserved.
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